The Wnt canonical signal transduction pathway is essential for a variety of biological/cellular processes including tissue differentiation and neuronal development. Aberrations in the pathway have been implicated in numerous pathologies such as cancer and various neurodegenerative conditions including Alzheimers disease (AD). The Wnt canonical pathway plays a major role in regulating the activity of glycogen synthase kinase 3 (GSK3). GSK3 is a "master" kinase capable of phosphorylating/regulating over 40 different proteins and has been implicated in generating aberrantly hyperphosporylated tau proteins associated with AD and other tauopathies. Hence, identifying the mechanisms and proteins that regulate GSK3 activity will provide pertinent pathological information underlying tau based neurpatholgoies such as AD and potential therapies. Low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) is a single pass transmembrane receptor that functions as a required co-receptor in the Wnt canonical pathway and whose inhibition in the pathway has recently been implicated in AD. LRP6 can function at the cell surface (membrane bound) and its intracellular domain (ICD) can be released from the membrane via proteolytic processing to form a biologically active LRP6-ICD. The released LRP6-ICD can inhibit aberrant phosphorylation of tau by GSK3 as well as constitutively activate the Wnt canonical pathway. However, the biological mechanism (i.e. protein-protein interaction), cellular location of action (i.e. cytosol and/or nucleus) and regulation of LRP6- ICD actions (i.e. phosphorylation, localization, etc) is unclear. The long-term objective and central hypothesis of this application is to determine the biological processes underlining LRP6-ICD activity, which will provide a better understanding of tau based neuropathologies associated with aberrant GSK3 activity. The project objective will be accomplished through three specific aims: 1) is phosphorylation of LRP6-ICD required for its function, 2) whats the function of LRP6-ICD in the nucleus, and 3) can LRPS-feD.lnhibit aberrant GSK3 mediated tau phosphorylation. A combination of in vitro and in situ cell culture models expressing various LRP6-ICD constructs will be used for specific aims 1 and 2 while specific aim 3 will be accomplished using an AD mouse model infected with LRP6-ICD constructs. Aberrant GSK3 activity likely contributes to the neuropathology of AD. The financial (currently $100 billion) and medical burden that this disease poses to public health can not be overstated. Therefore, understanding how proteins such as LRP6-ICD can abrogate aberrant GSK3 activity will identify relevant therapeutic targets for AD treatment.